JP4633462B2 - Method for producing 3-halo-4,5-dihydro-1H-pyrazole - Google Patents

Abstract

This invention relates to 3-sulfonate-4,5dihydro-1 H -pyrazole compounds of Formula (IIa). This invention also discloses preparation of compounds of Formula la comprising contacting a compound of Formula IIa with a compound of Formula HX 1 . This invention also discloses preparation of compounds of Formula (III) wherein X 1 , R 3 , R 6 , R 7 , R 8a , R 8b , and n are as defined in the disclosure.

Description

  There is a need for further methods for preparing 3-halo-4,5-dihydro-1H-pyrazole. Such compounds include useful intermediates for the production of crop protection agents, pharmaceuticals and other fine chemicals.

  Several methods have been reported for the preparation of 3-halo-4,5-dihydro-1H-pyrazole. For example, Non-Patent Document 1 reports the production of 3-chloro-4,5-dihydro-1H-pyrazole by contacting the corresponding oxo-pyrazolidine with phosphorus oxychloride. Non-Patent Document 2 describes the production of 3-chloro-4,5-dihydro-1H-pyrazole via a diazonium salt intermediate produced from the corresponding 3-amino-4,5-dihydro-1H-pyrazole. Disclose. Non-Patent Document 3 discloses 3-chloro-4,5 by dipolar ring addition of an acrylate ester with a hydrazidoyl chloride intermediate formed by decarboxylation chlorination of a hydrazone of glyoxylic acid using N-chlorosuccinimide. -The preparation of dihydro-1H-pyrazole is disclosed. In particular, there remains a need for alternative methods that use a relatively low cost reagent that is a wide range of chemical structure universal methods and is commercially available in industrial quantities.

J. et al. P. J.P. Chupp, Journal of Heterocyclic Chem. 1994, 31, 1377-1380 M.M. V. MV Gorelik et al., Journal of Organic Chemistry, U.S.A. S. S. R. 1985, 21, 773-781 (English translation of Zhurn Organicichekoi Kimii 1985, 21 (4), 851-859) K. K. B. K. Bach et al., Tetrahedron 1994, 50 (25), 7543-7556.

Summary of the Invention

  The present invention provides compounds of formula I

[Wherein L is an optionally substituted carbon moiety,
Each R is independently selected from optionally substituted carbon moieties;
k is an integer of 0 to 4,
And X ¹ is a halogen]
The present invention relates to a method for producing a 3-halo-4,5-dihydro-1H-pyrazole compound.

  This method is represented by the formula II

[Wherein X ² is a halogen other than OS (O) _m R ¹ , OP (O) _p (OR ² ) ₂ or X ¹ ;
m is 1 or 2,
p is 0 or 1,
R ¹ is selected from alkyl and haloalkyl; and phenyl optionally substituted by 1 to 3 substituents optionally selected from alkyl and halogen, and each R ² is independently alkyl and haloalkyl; and Selected from phenyl optionally substituted by 1 to 3 substituents selected from alkyl and halogen]
Contacting a 4,5-dihydro-1H-pyrazole compound of the formula HX ^{1 with} a compound in the presence of a suitable solvent.

  The present invention also provides a compound of formula III

[Where:
X ¹ is halogen,
Each R ³ is independently C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ haloalkyl, C ₂ -C ₄ haloalkenyl. , _C 2 -C _{4 haloalkynyl,} C 3 -C ₆ halocycloalkyl, _{halogen, CN, NO 2, C 1} ~C 4 _alkoxy, C 1 -C _{4 haloalkoxy,} C 1 -C _{4 alkylthio, C} 1 ~ C _{4 alkylsulfinyl,} C 1 -C _{4 alkylsulfonyl,} C 1 -C _{4 alkylamino,} C 2 -C _{8 dialkylamino,} C 3 -C _{6 cycloalkylamino, (C} 1 _{~C 4} alkyl) _(C 3 ~ C ₆ cycloalkyl) _amino, C 2 -C _{4 alkylcarbonyl,} C 2 -C _{6 alkoxycarbonyl,} C 2 -C _{6 alkylaminocarbonyl,} C 3 -C A dialkylaminocarbonyl or _C 3 -C ₆ trialkylsilyl,
Z is N or CR ⁵ ;
R ⁵ is H or R ³ ,
R ⁶ is CH ₃ , F, Cl or Br;
R ⁷ is F, Cl, Br, I or CF ₃ ;
R ^8a is C ₁ -C ₄ alkyl;
R ^8b is H or CH ₃ and n is an integer from 0 to 3]
The compound of formula Ia

[Wherein R ⁴ is H or an optionally substituted carbon moiety]
The present invention also relates to a process for producing the compound.

  This method is characterized in that a compound of formula Ia (ie a subgenus of formula I) is prepared by the method described above.

DETAILED DESCRIPTION OF THE INVENTION In the description herein, the term “carbon moiety” refers to a group in which a carbon atom is connected to the backbone chain of a 4,5-dihydro-1H-pyrazole ring. When the carbon moieties L and R (including R ⁴ ) are substituents that are remote from the reaction center, they can encompass various carbon-based groups that can be produced by modern methods of synthetic organic chemistry. The methods of the present invention are generally applicable to a wide range of starting compounds of formula I and product compounds of formula II. One skilled in the art will recognize that certain groups are sensitive to hydrogen halides and can be converted under reaction conditions. One skilled in the art will also recognize that certain groups are basic and can form salts with hydrogen halides, and thus the process of the present invention may require additional hydrogen halides.

  Thus, “carbon moiety” includes alkyl, alkenyl and alkynyl, which can be straight or branched. “Carbon moiety” also includes carbocycles and heterocycles, which can be saturated, partially saturated or fully unsaturated. Furthermore, the unsaturated ring can be aromatic if the Hückel rule is satisfied. The carbocycle and heterocycle of the carbon moiety can form a polycyclic ring system comprising multiple rings linked together. The term “carbocycle” refers to a ring in which the atoms forming the ring skeleton chain are selected from carbon only. The term “heterocycle” refers to a ring in which at least one of the ring skeleton chain atoms is other than carbon. A “saturated carbocycle” refers to a ring having a skeletal chain composed of carbon atoms connected to the other by a single bond, and unless otherwise specified, the remaining carbon valence is occupied by hydrogen atoms. The term “aromatic ring system” refers to fully unsaturated carbocycles and heterocycles in which at least one ring of the polycyclic ring system is aromatic. Aromatic is when each ring atom is essentially in the same plane and has a p-orbital perpendicular to the ring plane, and (4n + 2) π electrons are where n is 0 or a positive integer Represents obeying the Hückel rule in relation to the ring. The term “aromatic carbocyclic system” includes fully aromatic carbocyclic rings and carbocyclic rings in which at least one ring of the polycyclic ring system is aromatic. The term “non-aromatic carbocyclic ring system” refers to fully saturated carbocycles as well as partially or fully unsaturated carbocycles in which none of the rings in the ring system is aromatic. The terms “aromatic heterocycle” and “aromatic heterocycle” include fully aromatic heterocycles and heterocycles in which at least one ring of the polycyclic ring system is aromatic. The term “non-aromatic heterocycle” refers to fully saturated heterocycles as well as partially or fully unsaturated heterocycles in which none of the rings in the ring system is aromatic. The term “aryl” refers to a carbocyclic or heterocyclic ring or ring system in which at least one ring is aromatic and the aromatic ring provides a link to the rest of the molecule.

The carbon moieties specified for L, R and R ⁴ may be optionally substituted. The term “optionally substituted” in relation to these carbon moieties refers to carbon moieties that are unsubstituted or have at least one substituent other than hydrogen. Illustrative optional substituents are each optionally further substituted, alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, hydroxycarbonyl, formyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkoxycarbonyl, Hydroxy, alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy, aryloxy, alkylthio, alkenylthio, alkynylthio, cycloalkylthio, arylthio, alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, cycloalkylsulfinyl, arylsulfinyl, alkylsulfonyl, alkenylsulfonyl , Alkynylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, Mino, alkylamino, alkenylamino, alkynylamino, arylamino, aminocarbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkynylaminocarbonyl, arylaminocarbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkynylaminocarbonyl, arylaminocarbonyloxy, Alkoxycarbonylamino, alkenyloxycarbonylamino, alkynyloxycarbonylamino and aryloxycarbonylamino; and halogen, cyano, and nitro. Any further substituents are independent of groups such as those described above with respect to the substituents themselves to provide additional substituents for L, R and R ⁴ , such as haloalkyl, haloalkenyl and haloalkoxy. To be selected. As a further example, alkylamino can be further substituted with alkyl to give dialkylamino. A molecule that figuratively removes one or two hydrogen atoms from each or one of the two substituents and supports the molecular structure and connects the groups to support the substituents. Substituents can also be attached together to produce cyclic and polycyclic structures fused or attached to the structure. For example, a fused dioxolane structure containing a linking group —O—CH ₂ —O— is obtained by linking adjacent hydroxy groups and methoxy groups bonded to the phenyl ring together. Cyclic ethers containing epoxides can be obtained by linking together a hydroxy group and the molecular structure to which it is bonded. Illustrative substituents also include oxygen, which forms a carbonyl functionality when attached to carbon. Similarly, sulfur forms a thiocarbonyl functionality when attached to carbon. Rings and polycyclic structures can be formed by linking substituents together within the carbon moiety L or R. Embodiments in which at least two R moieties, or L moieties and at least one R moiety are contained in the same group (ie, a ring system is formed) are also illustrative of the carbon moieties L and R. When the 4,5-dihydropyrazole moiety constitutes one ring, two closely spaced R or L and R moieties contained in the same group result in a fused bicyclic or polycyclic ring system . Two geminal configuration R moieties contained in the same group yield a spiro ring system.

As described herein, the term “alkyl” used either alone or in combination words such as “alkylthio” or “haloalkyl” includes methyl, ethyl, n-propyl, i-propyl Or linear or branched alkyl such as various butyl, pentyl or hexyl isomers. The term “1-2 alkyl” indicates that the available positions for one or two substitutions are independently selected alkyls. “Alkenyl” includes straight- or branched-chain alkenes such as ethenyl, 1-propenyl, 2-propenyl, and the various butenyl, pentenyl and hexenyl isomers. “Alkenyl” also includes polyenes such as 1,2-propadienyl and 2,4-hexadienyl. “Alkynyl” includes linear or branched alkynes such as ethynyl, 1-propynyl, 2-propynyl, and the various butynyl, pentynyl and hexynyl isomers. “Alkynyl” can also include a moiety composed of a plurality of triple bonds such as 2,5-hexadiynyl. “Alkoxy” includes, for example, methoxy, ethoxy, n-propyloxy, isopropyloxy, and the various butoxy, pentoxy and hexyloxy isomers. “Alkenyloxy” includes straight-chain or branched alkenyloxy moieties. Examples of “alkenyloxy” include H ₂ C═CHCH ₂ O, (CH ₃ ) ₂ C═CHCH ₂ O, (CH ₃ ) CH═CHCH ₂ O, (CH ₃ ) CH═C (CH ₃ ) CH. ₂ O and CH ₂ ═CHCH ₂ CH ₂ O. “Alkynyloxy” includes straight-chain or branched alkynyloxy moieties. Examples of “alkynyloxy” include HC≡CCH ₂ O, CH ₃ C≡CCH ₂ O and CH ₃ C≡CCH ₂ CH ₂ O. “Alkylthio” includes methylthio, ethylthio, and branched or straight chain alkylthio moieties such as various propylthio, butylthio, pentylthio and hexylthio isomers. “Alkylsulfinyl” includes both enantiomers of an alkylsulfinyl group. Examples of “alkylsulfinyl” include CH ₃ S (O), CH ₃ CH ₂ S (O), CH ₃ CH ₂ CH ₂ S (O), (CH ₃ ) ₂ CHS (O), and various butyls. Examples include sulfinyl, pentylsulfinyl and hexylsulfinyl isomers. Examples of “alkylsulfonyl” include CH ₃ S (O) ₂ , CH ₃ CH ₂ S (O) ₂ , CH ₃ CH ₂ CH ₂ S (O) ₂ , (CH ₃ ) ₂ CHS (O) ₂ , And various butylsulfonyl, pentylsulfonyl and hexylsulfonyl isomers. “Alkylamino”, “alkenylthio”, “alkenylsulfinyl”, “alkenylsulfonyl”, “alkynylthio”, “alkynylsulfinyl”, “alkynylsulfonyl” and the like are defined as in the above examples. Examples of “alkylcarbonyl” include C (O) CH ₃ , C (O) CH ₂ CH ₂ CH ₃ and C (O) CH (CH ₃ ) ₂ . Examples of “alkoxycarbonyl” include CH ₃ OC (═O), CH ₃ CH ₂ OC (═O), CH ₃ CH ₂ CH ₂ OC (═O), (CH ₃ ) ₂ CHOC (═O), As well as various butoxy or pentoxycarbonyl isomers. “Cycloalkyl” includes, for example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The term “cycloalkoxy” includes the same groups linked by an oxygen atom, such as cyclopentyloxy and cyclohexyloxy. “Cycloalkylamino” means that the amino nitrogen atom is bound to a cycloalkyl group and a hydrogen atom, and includes groups such as cyclopropylamino, cyclobutylamino, cyclopentylamino, and cyclohexylamino. “(Alkyl) (cycloalkyl) amino” means a cycloalkylamino group in which a hydrogen atom is substituted by an alkyl group. Examples include (methyl) (cyclopropyl) amino, (butyl) (cyclobutyl) amino. , (Propyl) cyclopentylamino, (methyl) cyclohexylamino and the like. “Cycloalkenyl” includes groups such as cyclopentenyl and cyclohexenyl, and groups having more than one double bond such as 1,3- and 1,4-cyclohexadienyl.

The term “halogen”, either alone or in combination with words such as “haloalkyl”, includes fluorine, chlorine, bromine or iodine. The term “1-2 halogen” indicates that the positions available for one or two substitutions are independently selected halogens. Furthermore, when used in a combined word such as “haloalkyl”, said alkyl may be partially or fully substituted by halogen atoms which may be the same or different. Examples of “haloalkyl” include F ₃ C, ClCH ₂ , CF ₃ CH ₂ and CF ₃ CCl ₂ .

The total number of carbon atoms in the substituent is represented by the prefix “C _i -C _j ”, where i and j are, for example, numbers from ₁ to ₃ , for example, C ₁ -C ₃ alkyl is from methyl Indicates propyl.

Although there is no specific limitation on the size of Formulas I and II suitable for the methods of the present invention, typically Formula II is 4-100, more commonly 4-50, and most commonly 4-25. Carbon atoms, and 3-25, more typically 3-15, and most typically 3-10 heteroatoms. The heteroatoms are generally selected from halogen, oxygen, sulfur, nitrogen and phosphorus. The two heteroatoms of formulas I and II are dihydropyrazole ring nitrogen atoms, X ¹ is a halogen, and X ² contains at least one heteroatom.

Although there is no definite limitation on the L and the magnitude of R (including R ^4), L and R (including R ⁴⁾ If which may be alkyl moiety substituted in generally, 1 It contains 6 carbon atoms, more usually 1 to 4 carbon atoms, and most commonly 1 to 2 carbon atoms in the alkyl chain. The optionally substituted alkenyl and alkynyl moieties in L and R (including R ⁴ ) are generally 2 to 6 carbon atoms, more typically 2 to 4 carbon atoms, and most Generally it contains 2 to 3 carbon atoms in the alkenyl or alkynyl chain.

Also, although there is no clear limitation on the size of the groups described for R ¹ and R ² , alkyls including derivatives such as alkoxy and haloalkyl are generally C ₁ -C ₆ , more commonly C ₁ -C _4, and most commonly _C 1 -C _2.

As indicated above, the carbon moieties L, R, and R ⁴ are (among others) an aromatic ring or ring system. Examples of aromatic rings or ring systems include phenyl rings, 5-membered or 6-membered aromatic heterocycles, aromatic 8-membered, 9-membered or 10-membered fused carbobicyclo ring systems and aromatic 8-membered, 9-membered or 10-membered Examples include fused hexabicyclo ring systems, wherein each ring or ring system may be optionally substituted. The term “optionally substituted” in relation to these L and R carbon moieties refers to carbon moieties that are unsubstituted or have at least one substituent other than hydrogen. These carbon moieties may be substituted with as many optional substituents as applicable by substituting hydrogen atoms with substituents other than hydrogen on any available carbon or nitrogen atom. In general, the number of optional substituents (if present) ranges from 1 to 4. An example of a phenyl optionally substituted by 1 to 4 substituents is the ring described as U-1 in Presentation 1, where R ^v is any substituent other than hydrogen. , And r is an integer of 0-4. Examples of aromatic 8-membered, 9-membered or 10-membered fused carbobicyclo ring systems optionally substituted by 1 to 4 substituents are optionally described as U-85 in Presentation 1. A naphthyl group optionally substituted by 4 substituents, and a 1,2,3,4-tetrahydronaphthyl group optionally substituted by 1 to 4 substituents, optionally described as U-86 Where R ^v is any substituent and r is an integer from 0-4. Examples of 5- or 6-membered aromatic heterocycles optionally substituted by 1 to 4 substituents include the rings U-2 to U-53 described in Presentation 1, where R ^v is any substituent and r is an integer from 1 to 4. Examples of aromatic 8-, 9- or 10-membered fused heterobicyclo ring systems optionally substituted by 1 to 4 substituents include rings U-54 to U-84 described in Presentation 1. Where R ^v is any substituent and r is an integer from 0-4. Other examples of L and R include a benzyl group optionally substituted by 1 to 4 substituents described as U-87 in Presentation 1, and optionally 1 described as U-88. Benzoyl groups which may be substituted by ˜4 substituents are mentioned, wherein R ^v is any substituent and r is an integer from 0-4.

Although the structure U-I through U-85 is R ^v groups are shown, they are for an optional substituent, it need not be present should be noted. Nitrogen atoms that require substitution to fill their valence are substituted by H or R ^v . It should be noted here that some U groups can only be substituted by less than 4 R ^v groups (eg, U-14, U-15, U-18 to U-21 and U-). 32~U-34 can only be substituted with one ^{R v).} It should be noted here that when the point of attachment between (R ^v ) _r and the U group is not fixed, (R ^v ) _r is any available carbon of the U group. It can be bonded to an atom or a nitrogen atom. It should be noted here that if the point of attachment on the U group is shown unfixed, the U group can be represented by the substitution of a hydrogen atom through any available carbon of the U group. Be able to bind to the rest of I and II.

As indicated above, the carbon moieties L, R, and R ⁴ are (among others) saturated or partially saturated carbocycles and heterocycles, which may be further optionally substituted. The term “optionally substituted” in relation to these L and R carbon moieties refers to carbon moieties that are unsubstituted or have at least one substituent other than hydrogen. These carbon moieties may be substituted with as many optional substituents as applicable by substituting hydrogen atoms with substituents other than hydrogen on any available carbon or nitrogen atom. In general, the number of optional substituents (if present) ranges from 1 to 4. Examples of saturated or partially saturated carbocyclic, optionally include good C ₃ -C ₈ cycloalkyl optionally substituted optionally C ₃ -C ₈ cycloalkyl and optionally substituted. Examples of saturated or partially saturated heterocyclic rings include optionally substituted one or two ring members selected from the group consisting of C (═O), SO or S (O) _2. An optional 5-membered or 6-membered non-aromatic heterocycle is mentioned. Examples of such L and R carbon moieties include those described as G-1 to G-35 in Presentation 2. It should be noted here that if the point of attachment in these G groups is illustrated as unfixed, by substituting a hydrogen atom through any available carbon or nitrogen of the G group, The group is capable of binding to the remainder of formulas I and II. By substituting a hydrogen atom, any substituent can be attached to any available carbon or nitrogen (since the substituent is an optional substituent and is not described in Presentation 2). It should be noted here that when G comprises a ring selected from G-24 to G-31, G-34 and G-35, Q ² is O, S, NH or substituted. N may be selected.

L, and the R and R ⁴ carbon moieties may be optionally substituted is noteworthy. As noted above, the L and R carbon moieties may generally include, among other things, a U group or a G group, optionally further substituted with 1 to 4 substituents. Thus, the L and R carbon moieties may contain a U or G group selected from U-1 to U-88 or G-1 to G-35 and contain 1 to 4 U or G groups. Are further substituted by additional substituents (which may be the same or different), and both the core U or G group and the substituent U or G group may optionally be further substituted. . Of particular note here is the L carbon moiety comprising a U group optionally substituted by 1 to 3 additional substituents. For example, L can be a group U-41.

As shown in Scheme 1, according to the method of the present invention, 4,5-dihydro-1H-pyrazole of formula II is contacted with HX ¹ to give various 3-halo-4,5-dihydro-1H— of formula I. A pyrazole compound is formed.

In which L, R, X ¹ , X ² and k are as defined in the Summary of the Invention.

Run the reaction in a suitable solvent. For best results, the solvent should be non-nucleophilic, should be relatively inert to HX ¹ and should be able to dissolve the compound of formula II. Suitable solvents include dibromomethane, dichloromethane, acetic acid, ethyl acetate and acetonitrile. The reaction can be carried out in a pressure vessel at or near atmospheric pressure or above atmospheric pressure. HX ¹ starting material can be added in gaseous form to a reaction mixture containing a Formula II compound and a solvent. When X ² of the compound of formula II is a halogen such as Cl, the reaction is preferably carried out in such a way that HX ² generated by the reaction is removed by sparging or other suitable means. Alternatively, the HX ¹ starting material can be dissolved in an inert solvent (eg, acetic acid) that is highly soluble prior to contacting the compound of formula II, either as such or in solution. Also, when X ² of the compound of Formula II is a halogen such as Cl, substantially more than 1 equivalent of HX ¹ (eg, 4-10 equivalents) is typically required depending on the level of conversion desired. Is done. When X ² is OS (O) _m R ¹ or OP (O) _p (OR ² ) ₂ , 1 equivalent of HX ¹ can provide high conversion, but the compound of Formula II has at least one basic functionality More than one equivalent of HX ¹ is typically required when comprising a property (eg, a nitrogen-containing heterocycle). The reaction can be carried out between about 0 ° C. and 100 ° C., most conveniently near ambient temperature (eg about 10 ° C. to 40 ° C.) and most preferably between about 20 ° C. and 30 ° C. . The reaction can be facilitated by the addition of a Lewis acid catalyst (eg, aluminum bromide for the preparation of Formula I where X ¹ is Br). The product of formula I is isolated by conventional methods known to those skilled in the art including extraction, distillation and crystallization.

For the method of the present invention, preferred starting compounds include compounds of formula II where m is 2 and p is 1. Also preferred are compounds of formula II where X ² is halogen or OS (O) _m R ¹ (especially m is 2). More preferably, X ² is Cl or OS (O) _m R ¹ , m is 2, and R ¹ is optionally selected from C ₁ -C ₆ alkyl, CF ₃ , or C ₁ -C ₄ alkyl. Is a phenyl optionally substituted by 1 to 3 substituents, and more preferably R ¹ is a starting compound of formula II wherein C ₁ -C ₂ alkyl, phenyl or 4-methylphenyl . Particularly preferred methods of the invention are those using starting compounds of formula II where X ² is Cl or OS (O) ₂ R ¹ and R ¹ is methyl, phenyl or 4-methylphenyl. Can be mentioned. Particularly preferred methods of the invention include those using starting compounds of formula II where X ² is Cl or OS (O) ₂ R ¹ and R ¹ is phenyl or 4-methylphenyl. .

For the method of the present invention, preferred product compounds include compounds of formula I wherein X ¹ is Cl, Br or I. More preferred product compounds include compounds of formula I, wherein X ¹ is Cl or Br. Most preferred product compounds include compounds of formula I, wherein X ¹ is Br. In a particularly useful embodiment of the method of the invention, X ² is OS (O) ₂ R ¹ and R ¹ is, for example, methyl, phenyl or 4-methylphenyl, more preferably phenyl or 4- The preparation of a compound of formula I wherein X ¹ is Cl or Br from a compound of formula II which is methylphenyl.

  Preferred methods of the invention include those where the starting compound of formula II is formula IIa and the resulting compound of formula I is formula Ia, as shown in Scheme 2 below.

In which X ¹ and X ² are as defined for formulas I and II;
Each R ³ is independently C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ haloalkyl, C ₂ -C ₄ haloalkenyl. , _C 2 -C _{4 haloalkynyl,} C 3 -C ₆ halocycloalkyl, _{halogen, CN, NO 2, C 1} ~C 4 _alkoxy, C 1 -C _{4 haloalkoxy,} C 1 -C _{4 alkylthio, C} 1 ~ C _{4 alkylsulfinyl,} C 1 -C _{4 alkylsulfonyl,} C 1 -C _{4 alkylamino,} C 2 -C _{8 dialkylamino,} C 3 -C _{6 cycloalkylamino, (C} 1 _{~C 4} alkyl) _(C 3 ~ C ₆ cycloalkyl) _amino, C 2 -C _{4 alkylcarbonyl,} C 2 -C _{6 alkoxycarbonyl,} C 2 -C _{6 alkylaminocarbonyl,} C 3 -C A dialkylaminocarbonyl or _C 3 -C ₆ trialkylsilyl,
R ⁴ is H or an optionally substituted carbon moiety,
Z is N or CR ⁵ ;
R ⁵ is H or R ³ and n is an integer selected from 0 to 3.

  One skilled in the art will recognize that Formula Ia is a subgenus of Formula I and that Formula IIa is a subgenus of Formula II.

A wide range of optionally substituted carbon moieties that have already been described are useful as R ⁴ of the ester of formula Ia with respect to the method of Scheme 2, but generally R ⁴ is from alkyl, alkenyl and alkynyl. Selected groups containing up to 18 carbon atoms; and benzyl and phenyl, each optionally substituted by alkyl and halogen. Most preferred R ⁴ is C ₁ -C ₄ alkyl.

Of note is the method shown in Scheme 2 wherein Z is N, n is 1 and R ³ is Cl or Br and is in the 3 position. Also of note is the process shown in Scheme 2, wherein X ² is halogen or OS (O) ₂ R ¹ , and particularly R ¹ is methyl, phenyl or 4-methylphenyl. Also of note is the method shown in Scheme 2, where X ¹ is Br or Cl, and in particular X ¹ is Br. Of particular note, in Scheme 2, where X ¹ is Br, X ² is Cl or OS (O) _m R ¹ , m is 2 and R ¹ is phenyl or 4-methylphenyl. It is the method shown.

When basic functionality is present in the compound of formula IIa (ie, Z is N and / or R ³ is alkylamino, dialkylamino, cycloalkylamino or (alkyl) (cycloalkyl) amino) More than one equivalent of HX ¹ is typically required for sufficient conversion even when X ² is OS (O) _m R ¹ or OP (O) _p (OR ² ) ₂ . In formula IIa, when Z is N, R ³ is other than alkylamino, dialkylamino, cycloalkylamino and (alkyl) (cycloalkyl) amino and X ² is S (O) ₂ R ¹ , 1.5-2 using fewer HX ¹ of about equivalent, very good conversion is obtained.

As shown in Scheme 3, from the corresponding compound of formula 1, starting compounds of formula II where X ² is halogen can be prepared.

Where X ² is halogen and L, R and k are as previously described.

  Usually, treatment of a compound of formula 1 with a halogenating agent in the presence of a solvent provides the corresponding halo compound of formula II. Usable halogenating agents include phosphorus oxyhalide, phosphorus trihalide, phosphorus pentahalide, thionyl chloride, dihalotrialkylphosphorane, dihalodiphenylphosphorane, oxalyl chloride, phosgene, sulfur tetrafluoride, And trifluoride (diethylamino) sulfur. Phosphorus oxyhalides and phosphorus pentahalides are preferred. In order to obtain a complete conversion, at least 0.33 equivalents relative to the compound of formula 1 (ie the molar ratio of phosphorus oxyhalide to formula 1 is at least 0.33), preferably about 0.33 and 1 An equivalent amount of phosphorus oxyhalide between .2 should be used. In order to obtain complete conversion, at least 0.20 equivalents, preferably between about 0.20 and 1.0 equivalents of phosphorus halide, should be used relative to the compound of formula 1. Typical solvents for this halogenation include halogenated alkanes such as dichloromethane, chloroform, chlorobutane, aromatic solvents such as benzene, xylene, chlorobenzene, tetrahydrofuran, p-dioxane, diethyl ether and the like. And a polar aprotic solvent such as acetonitrile, N, N-dimethylformamide and the like. Optionally, an organic base such as triethylamine, pyridine, N, N-dimethylaniline, etc. can be added. The addition of a catalyst such as N, N-dimethylformamide is also optional. A method in which the solvent is acetonitrile and no base is present is preferred. Typically, when an acetonitrile solvent is used, neither a base nor a catalyst is required. A preferred method is carried out by mixing the compound of formula 1 in acetonitrile. The halogenating agent is then added over a convenient time and then the mixture is held at the desired temperature until the reaction is complete. The reaction temperature is typically between about 20 ° C. and the boiling point of acetonitrile, and the reaction time is typically less than 2 hours. The reactants are then neutralized with an inorganic base such as sodium bicarbonate, sodium hydroxide, or an organic base such as sodium acetate. The desired product, a compound of formula II, can be isolated by methods known to those skilled in the art including, for example, extraction, crystallization or distillation.

As shown in Scheme 4, X ³ S (O) _m R ¹ (2) or X ³ P (O) _p (OR ² ) ₂ (3) (X ³ is a nucleophilic reaction leaving group, respectively. The compound of formula II in which R ¹ is also OS (O) _m R ¹ or OP (O) _p (OR ² ) ₂ from the corresponding starting compound of formula 1 by contacting with Can do. For X ³ , halides such as Cl are particularly useful. Also useful is X ³ S (O) _m R ¹ where X ³ is OS (O) _m R ¹ (ie, Formula 2 is R ¹ S (O) _m OS (O) _m R ¹ ). Yes, X ³ which is OS (O) _m R ¹ is particularly useful when R ¹ is CF ₃ . From the viewpoint that synthesis reachability and relatively low cost, X ³ is Cl is generally preferred.

Where X ² is OS (O) _m R ¹ or OP (O) _p (OR ² ) ₂ , X ³ is a leaving group, and L, R, R ¹ , k, m and p are As defined above.

In this method, the compound of Formula 1 is converted to Formula 2 (for X ² which is OS (O) _m R ¹ ) or Formula 3 (OP (O) _p (OR ² ), typically in the presence of a solvent and a base. With respect to X ₂ which is ² ). Suitable solvents include dichloromethane, tetrahydrofuran, acetonitrile and the like. Suitable bases include tertiary amines (eg, triethylamine, N, N-diisopropylethylamine) and ionic bases such as potassium carbonate. A tertiary amine is preferred as the base. In order to obtain a complete conversion, generally at least one equivalent of a compound of formula 2 or formula 3 and a base (preferably a slight excess, eg 5-10%) compared to the compound of formula 1 use. The reaction is typically carried out at a temperature between about −50 ° C. and the boiling point of the solvent, more generally between about 0 ° C. and ambient temperature (ie, about 15 ° C. to 30 ° C.). The reaction is typically complete in 2 hours to several days and the progress of the reaction can be monitored by techniques known to those skilled in the art such as thin layer chromatography and ¹ H NMR spectral analysis. The reaction mixture is then finished, for example by washing with water, drying the organic phase and evaporating the solvent. The desired product, a compound of formula II, can be isolated by methods known to those skilled in the art including extraction, crystallization and distillation.

  Since Formula IIa is a subgenus of Formula II, the compound of Formula IIa can be prepared from the corresponding compound of Formula 1a, which is a subgenus of Formula 1, by the methods already described with respect to Schemes 3 and 4.

In which R ³ , R ⁴ , Z and n are as defined for formula IIa.

  Compounds of formula 1 can be prepared by various modern synthetic methodologies known to those skilled in the art. For example, as outlined in Scheme 5, compounds of formula 1a can be prepared from compounds of formulas 4 and 5.

In which R ³ , R ⁴ , Z and n are as defined for formula IIa.

In this method, a hydrazine compound of formula 4 is contacted with a compound of formula 5 (a fumarate ester or a maleate ester or mixtures thereof may be used) in the presence of a base and a solvent. The base is typically a metal alkoxide salt such as sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, potassium tertiary butoxide, lithium tertiary butoxide and the like. More than 0.5 equivalents, preferably between 0.9 and 1.3 equivalents of base to the compound of formula 4 should be used. More than 1.0 equivalent of a compound of formula 5 should be used, preferably between 1.0 and 1.3. Polar protic and polar aprotic organic solvents such as alcohol, acetonitrile, tetrahydrofuran, N, N-dimethylformamide, dimethyl sulfoxide and the like can be used. Preferred solvents are alcohols such as methanol and ethanol. Particularly preferred are alcohols which are the same as in the preparation of fumarate or maleate and alkoxide bases. The reaction is typically carried out by mixing the compound of formula 4 with a base in a solvent. The mixture can be heated or cooled to the desired temperature, and the compound of formula 5 can be added over time. Typically, the reaction temperature is between 0 ° C. and the boiling point of the solvent used. In order to increase the boiling point of the solvent, the reaction may be carried out under a pressure higher than atmospheric pressure. A temperature between about 30 ° C. and 90 ° C. is typically preferred. As long as heat transfer is possible, the addition time can be rapid. Typical addition times are between 1 minute and 2 hours. Depending on the identity of the compounds of Formula 4 and Formula 5, the optimum reaction temperature and addition time will vary. After the addition, the reaction mixture can be held for a while at the reaction temperature. Depending on the reaction temperature, the required holding time may be from 0 to 2 hours. Typical retention times are 10 to 60 minutes. The reaction can then be acidified by adding an organic acid such as acetic acid or the like or an inorganic acid such as hydrochloric acid, sulfuric acid or the like. Depending on the reaction conditions and means of isolation, the —CO ₂ R ⁴ functionality of the compound of formula 1a can be hydrolyzed to —CO ₂ H, for example when water is present in the reaction mixture. Can be promoted. When a carboxylic acid (—CO ₂ H) is formed, it is converted to —CO ₂ R ⁴ where R ⁴ is, for example, C ₁ -C ₄ alkyl, using esterification methods well known in the art. Can do. The desired product, compound of formula 1a, can be isolated by methods known to those skilled in the art such as crystallization, extraction or distillation.

Those skilled in the art using the foregoing will be able to utilize the invention to its fullest extent. Accordingly, the following examples are to be construed as merely illustrative and are not intended to limit the present disclosure to any form. The steps in the following examples describe the procedure for each step in the total synthetic transformation, and the starting materials for each step are not necessarily manufactured by the specific manufacturing execution described in the other examples or steps. May be. Percentages are by weight except for chromatographic solvent mixtures or unless otherwise specified. Unless otherwise noted, parts and percentages with respect to chromatographic solvent mixtures are by volume. ¹ H NMR spectra are reported at ppm low magnetic fields from tetramethylsilane. “S” means singlet, “d” means doublet, “t” means triplet, “q” means quartet, “m” means multiplet "Dd" means doublet doublet, "dt" means triplet doublet, and "br s" means broad singlet.

Example 1
Production Step A of 2-bromo-1- (3-chloro-2-pyridinyl) -4,5-dihydro-1H-pyrazole-5-carboxylate by replacing chlorine with bromine A: 2- (3- Preparation of ethyl chloro-2-pyridinyl) -5-oxo-3-pyrazolidinecarboxylate A 2 L 4-neck flask equipped with a mechanical stirrer, thermometer, addition funnel, reflux condenser and nitrogen inlet was charged with absolute ethanol ( 250 mL) and sodium ethoxide in ethanol (21%, 190 mL, 0.504 mol) were charged. The mixture was heated to reflux at about 83 ° C. It was then treated with 3-chloro-2 (1H) -pyridinone hydrazone (68.0 g, 0.474 mol). The mixture was reheated and refluxed for 5 minutes. The yellow slurry was then treated dropwise with diethyl maleate (88.0 mL, 0.544 mol) over 5 minutes. During the addition, the reflux rate increased significantly. By the end of the addition, all starting material was dissolved. The resulting red orange solution was held under reflux for 10 minutes. After cooling to 65 ° C., the reaction mixture was treated with glacial acetic acid (50.0 mL, 0.873 mol). A precipitate formed. Dilution of the mixture with water (650 mL) resulted in dissolution of the precipitate. The orange solution was cooled with an ice bath. The product started to precipitate at 28 ° C. The slurry was held at about 2 ° C. for 2 hours. The product was isolated by filtration, washed with aqueous ethanol (40%, 3 × 50 mL) and then air dried on the filter for about 1 hour. The title product compound was obtained as a highly crystalline light orange powder (70.3 g, 55% yield). ^No significant impurities were observed by ¹ H NMR.
¹ H NMR (DMSO-d ₆ ) δ 1.22 (t, 3H), 2.35 (d, 1H), 2.91 (dd, 1H), 4.20 (q, 2H), 4.84 (d , 1H), 7.20 (dd, 1H), 7.92 (d, 1H), 8.27 (d, 1H), 10.18 (s, 1H).

Step B: Preparation of ethyl 3-chloro-1- (3-chloro-2-pyridinyl) -4,5-dihydro-1H-pyrazole-5-carboxylate equipped with a mechanical stirrer, thermometer, reflux condenser and nitrogen inlet. Into a 2 L 4-necked flask was added acetonitrile (1000 mL), ethyl 2- (3-chloro-2-pyridinyl) -5-oxo-3-pyrazolidinecarboxylate (ie, the product of Step A) (91. 0 g, 0.337 mol) and phosphorus oxychloride (35.0 mL, 0.375 mol) were charged. Upon addition of phosphorus oxochloride, the mixture spontaneously exothermed from 22 ° C. to 25 ° C. and a precipitate formed. The pale yellow slurry was heated to reflux at 83 ° C. for 35 minutes, at which time the precipitate dissolved. The resulting orange solution was held under reflux for 45 minutes, at which time it turned black-green. The reflux condenser was replaced with a distillation head and 650 mL of solvent was removed by distillation. A second 2 L four-necked flask equipped with a mechanical stirrer was charged with sodium bicarbonate (130 g, 1.55 mol) and water (400 mL). Over 15 minutes, the concentrated reaction mixture was added to the sodium bicarbonate slurry. The resulting biphasic mixture was stirred vigorously for 20 minutes, at which point gas evolution ceased. The mixture was diluted with dichloromethane (250 mL) and then stirred for 50 minutes. The mixture was treated with Celite® 545 diatomaceous filter aid (11 g) and then filtered to remove black tar-like material that inhibits phase separation. The filtrate was slow to separate into separate phases, so it was diluted with dichloromethane (200 mL) and water (200 mL) and treated with additional Celite® 545 (15 g). The mixture was filtered and the filtrate was transferred to a separatory funnel. The heavier dark green organic layer was separated. The fragment layer (50 mL) was refiltered and then added to the organic layer. The organic solution (800 mL) was treated with magnesium sulfate (30 g) and silica gel (12 g) and the slurry was stirred magnetically for 30 minutes. The slurry was filtered to remove magnesium sulfate and silica gel and it became deep blue-green. The filter cake was washed with dichloromethane (100 mL). The filtrate was concentrated on a rotary evaporator. The product consisted of a dark amber oil (92.0 g, 93% yield). ^The only obvious impurities observed by ¹ H NMR were 1% starting material and 0.7% acetonitrile.
¹ H NMR (DMSO-d ₆ ) δ 1.15 (t, 3H), 3.26 (dd, 1H), 3.58 (dd, 1H), 4.11 (q, 2H), 5.25 (dd , 1H), 7.00 (dd, 1H), 7.84 (d, 1H), 8.12 (d, 1H).

Step C: Preparation of ethyl 3-bromo-1- (3-chloro-2-pyridinyl) -4,5-dihydro-1H-pyrazole-5-carboxylate 3-chloro-1- (3 in dibromomethane (85 mL) -Chloro-2-pyridinyl) -4,5-dihydro-1H-pyrazole-5-carboxylate (ie the product of Step B) (8.45 g, 29.3 mmol) was passed hydrogen bromide. did. After 90 minutes, the gas was turned off and the reaction mixture was washed with aqueous sodium bicarbonate (100 mL). The organic phase was dried and evaporated under reduced pressure to give the title product as an oil (9.7 g, 99% yield), which crystallized on standing.
¹ H NMR (CDCl ₃ ) δ 1.19 (t, 3H), 3.24 (1/2 of AB in ABX pattern, J = 9.3, 17.3 Hz, 1H), 3.44 (AB in ABX pattern) , J = 11.7, 17.3 Hz, 1H), 4.18 (q, 2H), 5.25 (ABX X, 1H, J = 9.3, 11.9 Hz), 6. 85 (dd, J = 4.7, 7.7 Hz, 1H), 7.65 (dd, J = 1.6, 7.8 Hz, 1H), 8.07 (dd, J = 1.6, 4.H). 8Hz, 1H).

Example 2
Preparation Step A of 1- (3- (3-bromo-1- (3-chloro-2-pyridinyl) -4,5-dihydro-1H-pyrazole-5-carboxylate by replacing tosylate with bromine Preparation of ethyl chloro-2-pyridinyl) -4,5-dihydro-3-[[(4-methyl-phenyl) sulfonyl] oxy] -1H-pyrazole-5-carboxylate 2 at 0 ° C. in dichloromethane (100 mL) -(3-Chloro-2-pyridinyl) -5-oxo-3-pyrazolidinecarboxylate (ie, the product of Example 1, Step A) (10.0 g, 37.1 mmol) and p-chloride Triethylamine (3.75 g, 37.1 mmol) was added dropwise into a mixture of toluenesulfonyl (7.07 g, 37.1 mmol). A further portion of p-toluenesulfonyl chloride (0.35 g, 1.83 mmol) and triethylamine (0.19 g, 1.88 mmol) was added. The reaction mixture was then warmed to room temperature and allowed to stir overnight. The mixture was then diluted with dichloromethane (200 mL) and washed with water (3 × 70 mL). The organic phase was dried and evaporated to leave the title product as an oil (13.7 g, 87% yield). This slowly formed crystals. The product recrystallized from ethyl acetate / hexane melted at 99.5-100 ° C.
IR (nujol): 1740, 1638, 1576, 1446, 1343, 1296, 1228, 1191, 1178, 1084, 1027, 948, 969, 868, 845 cm ⁻¹ .
¹ H NMR (CDCl ₃ ) δ 1.19 (t, 3H), 2.45 (s, 3H), 3.12 (1/2 of AB in the ABX pattern, J = 17.3, 9 Hz, 1H), 3 .33 (1/2 of AB in the ABX pattern, J = 17.5, 11.8 Hz, 1H), 4.16 (q, 2H), 5.72 (ABX X, J = 9, 11.8 Hz, 1H), 6.79 (dd, J = 4.6, 7.7 Hz, 1H), 7.36 (d, J = 8.4 Hz, 2H), 7.56 (dd, J = 1.6, 7 .8 Hz, 1H), 7.95 (d, J = 8.4 Hz, 2H), 8.01 (dd, J = 1.4, 4.6 Hz, 1H).

Step B: Preparation of ethyl 3-bromo-1- (3-chloro-2-pyridinyl) -4,5-dihydro-1H-pyrazole-5-carboxylate 1- (3-chloro-2 in dibromomethane (50 mL) -Pyridinyl) -4,5-dihydro-3-[[(4-methylphenyl) sulfonyl] oxy] -1H-pyrazole-5-carboxylate (ie the product of Step A) (5 g, 11.8 mmol) Hydrogen bromide was passed through the solution. After 60 minutes, the gas was turned off and the reaction mixture was washed with aqueous sodium bicarbonate (50 mL). The organic phase was dried and evaporated under reduced pressure to give the title product as an oil (3.92 g, 100% yield), which crystallized on standing. The ¹ H NMR spectrum of the product was identical to that reported for the product of Example 1, Step C.

Example 3
Process A for preparing ethyl 3-bromo-1- (3-chloro-2-pyridinyl) -4,5-dihydro-1H-pyrazole-5-carboxylate by replacing benzenesulfonate with bromine: 1- (3 Preparation of -chloro-2-pyridinyl) -4,5-dihydro-3-[(phenylsulfonyl) oxy] -1H-pyrazole-5-carboxylate 2- (3-chloro in dichloromethane (20 mL) at 0 ° C 2-pyridinyl) -5-oxo-3-pyrazolidinecarboxylate (ie, the product of Example 1, Step A) (5.0 g, 18.5 mmol) and benzenesulfonyl chloride (3.27 g, To the mixture (18.5 mmol), triethylamine (1.85 g, 18.5 mmol) was added dropwise over 1 hour. The temperature did not exceed 1 ° C. After stirring the reaction mixture for an additional 2 hours, a further portion of benzenesulfonyl chloride (0.5 g, 1.85 mmol) was added. A further portion of triethylamine (0.187 g, 1.85 mmol) was then added dropwise to the mixture. After stirring for 0.5 hour, the mixture was partitioned between water (100 mL) and dichloromethane (100 mL). The organic phase was dried (MgSO ₄ ) and evaporated to provide the title product as an orange solid (7.18 g, 94% yield). The product recrystallized from ethyl acetate / hexane melted at 84-85 ° C.
IR (Nujol): 1737, 1639, 1576, 1448, 1385, 1346, 1302, 1233, 1211, 1188, 1176, 1088, 1032, 944, 910, 868, 846 cm ⁻¹ .
¹ H NMR (CDCl ₃ ) δ 1.19 (t, 3H), 3.15 (1/2 of AB in the ABX pattern, J = 8.8, 17.3 Hz, 1H), 3.36 (AB in the ABX pattern) , J = 11.8, 17.3 Hz, 1H), 4.17 (q, 2H), 5.23 (ABX X, J = 8.8, 11.8 Hz, 1H), 6. 78 (dd, J = 2.8, 4.8 Hz, 1H), 7.71-7.55 (m, 4H), 8.01 (dd, J = 1.6, 4.6 Hz, 2H), 8 0.08 (dd, J = 1.0, 2.6 Hz, 2H).

Step B: Preparation of ethyl 3-bromo-1- (3-chloro-2-pyridinyl) -4,5-dihydro-1H-pyrazole-5-carboxylate 1- (3-Chloro-2-) in acetic acid (4 mL) A solution of pyridinyl) -4,5-dihydro-3-[(phenylsulfonyl) oxy] -1H-pyrazole-5-carboxylate (ie the product of Step A) (1.0 g, 2.44 mmol) To a solution of hydrogen bromide in acetic acid (33%, 1.2 g, 4.89 mmol). After about 1 hour, the reaction mixture was added to saturated aqueous sodium bicarbonate (100 mL). The mixture was then extracted with ethyl acetate (2 × 50 mL) and the combined extracts were dried (MgSO ₄ ) and evaporated to give the title product as an oil (0.69 g, 85% yield). sponsored. This slowly crystallized. ^{The 1} H NMR spectrum was identical to that reported for the product of Example 1, Step C.

  Along with methods known in the art, the procedures described herein can convert compounds of formula II to compounds of formula I as illustrated in Table 1 for formulas Ia and IIa. The following abbreviations are used in the table: t is tertiary, s is secondary, n is normal, i is iso, Me is methyl, Et is ethyl, Pr is propyl, i-Pr is Isopropyl, t-Bu is tertiary butyl, and Ph is phenyl.

Using the method for producing 3-halo-4,5-dihydro-1H-pyrazole of the present invention, a wide variety of formula I are useful as intermediates for producing crop protection agents, pharmaceuticals and other fine chemicals. Compounds can be produced. Presentation 3 includes OS (O) _m R ¹ (eg, OS (O) ₂ CH ₃ or OS (O) ₂ Ph), OP (O) _p (OR ² ) ₂ (eg, OP (O) (OMe) ₂ ), or the corresponding 4,5-dihydro-1H-pyrazole having various halogen substituents (eg, Cl substituting Br, or Br substituting Cl) 3 3-halo-4, which describes examples of -halo-4,5-dihydro-1H-pyrazole and is useful for producing products having fungicidal, fungicidal, herbicidal or plant growth regulating efficacy , 5-dihydro-1H-pyrazole. These examples are to be construed as illustrative of the various ranges of applicability of the method of the present invention, but are not intended to be limiting. Other compounds that can be produced according to the methods of the invention may be useful for the manufacture of pharmaceutical products such as anti-inflammatory agents, allergy inhibitors, anticonvulsants, sedatives, and the like.

  Among the compounds that can be prepared according to the method of the present invention, the compounds of formula Ia are particularly useful for the preparation of compounds of formula III.

Wherein Z, X ¹ , R ³ and n are as defined above, R ⁶ is CH ₃ , F, Cl or Br and R ⁷ is F, Cl, Br, I or CF ₃ ^Yes , R ^8a is C ₁ -C ₄ alkyl and R ^8b is H or CH ₃ . Preferably, Z is N, n is 1, and R ³ is Cl or Br and is in the 3 position.

  For example, PCT Gazette International Publication No. 01/70671 published September 27, 2001, and US Patent Application No. 60 / 324,173 filed September 21, 2001, filed September 21, 2001. The compounds of formula III are useful as insecticides as described in US Patent Application No. 60 / 323,941 and US Patent Application No. 60 / 369,661, filed Apr. 2, 2002. . The preparation of compounds of Formula 8 and Formula III is described in US Patent Application No. 60/400352, filed July 31, 2002 [BA9308 US PRV], and US Patent Application No. 60/100, filed February 11, 2003. 446438 [BA9308 US PRV1] and thereby incorporated herein by reference in its entirety; and described in US Patent Application No. 60 / 369,660, filed April 2,2002. ing.

  Compounds of formula III can be prepared from the corresponding compounds of formula Ia by the methods outlined in Schemes 6-9.

  As illustrated in Scheme 6, the compound of formula Ia is treated with an oxidizing agent, optionally in the presence of an acid.

In which R ³ , R ⁴ , Z, X ¹ and n are as defined above for formula Ia.

Preferred starting materials for this step are compounds of formula Ia where R ⁴ is C ₁ -C ₄ alkyl. The oxidizing agent can be hydrogen peroxide, organic peroxide, potassium persulfate, sodium persulfate, ammonium persulfate, potassium monopersulfate (eg, Oxone®) or potassium permanganate. In order to obtain complete conversion, a minimum of 1 equivalent, preferably about 1-2 equivalents of oxidizing agent should be used relative to the compound of formula Ia. This oxidation is typically carried out in the presence of a solvent. The solvent can be an ether such as tetrahydrofuran, p-dioxane, an organic ester such as ethyl acetate, dimethyl carbonate, or a polar aprotic organic such as N, N-dimethylformamide, acetonitrile, and the like. Suitable acids for use in the oxidation step include inorganic acids such as sulfuric acid, phosphoric acid, and organic acids such as acetic acid, benzoic acid, and the like. If used, the acid must be used in an equivalent weight higher than 0.1 relative to the compound of formula Ia. In order to obtain complete conversion, 1 to 5 equivalents of acid can be used. For compounds of formula Ia where Z is CR ⁵ , the preferred oxidant is hydrogen peroxide and preferably the oxidation is carried out in the absence of acid. For compounds of formula Ia where Z is N, the preferred oxidant is potassium persulfate and preferably the oxidation is carried out in the presence of sulfuric acid. The reaction can be carried out by mixing the compound of formula Ia in the desired solvent and, if used, the acid. The oxidant can then be added at a convenient rate. In order to obtain a suitable reaction time to complete the reaction, preferably less than 8 hours, the reaction temperature is typically varied from as low as about 0 ° C. to the boiling point of the solvent. The desired product, the compound of formula 6, can be isolated by methods known to those skilled in the art including extraction, chromatography, crystallization and distillation.

For example, a carboxylic acid compound of formula 6 in which R ⁴ is H can be prepared from the corresponding ester compound of formula 6 in which R ⁴ is C ₁ -C ₄ alkyl. Carboxylic ester compounds can be converted to carboxylic acid compounds by various methods, including nucleophilic cleavage under anhydrous conditions, or hydrolysis methods involving the use of either acids or bases (for method overview, see TW Greene and PGM Wuts, Protective Groups in Organic Synthesis, 2nd edition; John Willy & Johns, Inc. (See New York, 1991, pages 224-269). For compounds of formula 6, a base-catalyzed hydrolysis method is preferred. Suitable bases include alkali metal (eg, lithium, sodium or potassium) hydroxides. For example, the ester can be dissolved in a mixture of water and an alcohol such as ethanol. Treatment with sodium hydroxide or potassium hydroxide saponifies the ester to provide the sodium or potassium salt of the carboxylic acid. Oxidation with a strong acid such as hydrochloric acid or sulfuric acid provides a carboxylic acid of formula 6 where R ⁴ is H. The carboxylic acid can be isolated by methods known to those skilled in the art including extraction, distillation and crystallization.

Coupling of a pyrazole carboxylic acid of formula 6 where R ⁴ is H and an anthranilic acid of formula 7 provides a benzoxazinone of formula 8. In Scheme 7, sequential addition of methanesulfonyl chloride to a pyrazole carboxylic acid of formula 6 where R ⁴ is H in the presence of a tertiary amine such as triethylamine or pyridine, followed by addition of anthranilic acid of formula 7 , Followed by a second addition of tertiary amine and methanesulfonyl chloride to produce the benzoxazinone of formula 8 directly.

In which R ³ , R ⁶ , R ⁷ , X ¹ , Z and n are as defined for formula III.

  This procedure generally gives good yields of benzoxazinone.

  Scheme 8 shows another alternative of the benzoxazinone of formula 8 with the coupling of the pyrazole acid chloride of formula 10 and the isatoic anhydride of formula 9 to provide the benzoxazinone of formula 8 directly. Indicates manufacture.

In which R ³ , R ⁶ , R ⁷ , X ¹ , Z and n are as defined for formula III.

For this reaction, solvents such as pyridine or pyridine / acetonitrile are suitable. The acid chloride of formula 10 is available from the corresponding acid of formula 6 where R ⁴ is H by known procedures such as chlorination with thionyl chloride or oxalyl chloride.

As outlined in Scheme 9, the reaction of a benzoxazinone of formula 8 with a C ₁ -C ₄ alkylamine and (C ₁ -C ₄ alkyl) (methyl) amine of formula 11 produces a compound of formula III can do.

In which R ³ , R ⁶ , R ⁷ , R ^8a , R ^8b , X ¹ , Z and n are as defined above.

［式中、Ｌは場合により置換されていてもよい炭素部分であり、
各Ｒは独立して場合により置換されていてもよい炭素部分から選択され、
ｋは０〜４の整数であり、
そしてＸ¹はハロゲンである］
の３−ハロ−４，５−ジヒドロ−１Ｈ−ピラゾール化合物を製造する方法であって、
式ＩＩ

［式中、Ｘ²はＯＳ（Ｏ）_mＲ¹、ＯＰ（Ｏ）_p（ＯＲ²）₂またはＸ¹以外のハロゲンであり、
ｍは１または２であり、
ｐは０または１であり、
Ｒ¹はアルキルおよびハロアルキル；ならびに場合によりアルキルおよびハロゲンから選択される１〜３個の置換基によって置換されていてもよいフェニルから選択され、そして
各Ｒ²は独立してアルキルおよびハロアルキル；ならびに場合によりアルキルおよびハロゲンから選択される１〜３個の置換基によって置換されていてもよいフェニルから選択される］
の４，５−ジヒドロ−１Ｈ−ピラゾール化合物を、適切な溶媒の存在下で、式ＨＸ¹の化合物と接触させることを含んでなる方法。
２． ｍが２であり、そしてｐが１である上記１に記載の方法。
３． Ｘ²がハロゲンまたはＯＳ（Ｏ）_mＲ¹である上記２に記載の方法。
４． Ｘ²がＣｌまたはＯＳ（Ｏ）_mＲ¹であり、そしてＲ¹がＣ₁〜Ｃ₂アルキル、フェニルまたは４−メチルフェニルである上記３に記載の方法。
５． Ｘ¹がＣｌまたはＢｒである上記１に記載の方法。
６． 式Ｉの化合物が式Ｉａ

であり、そして式ＩＩの化合物が式ＩＩａ

［式中、
各Ｒ³は独立してＣ₁〜Ｃ₄アルキル、Ｃ₂〜Ｃ₄アルケニル、Ｃ₂〜Ｃ₄アルキニル、Ｃ₃〜Ｃ₆シクロアルキル、Ｃ₁〜Ｃ₄ハロアルキル、Ｃ₂〜Ｃ₄ハロアルケニル、Ｃ₂〜Ｃ₄ハロアルキニル、Ｃ₃〜Ｃ₆ハロシクロアルキル、ハロゲン、ＣＮ、ＮＯ₂、Ｃ₁〜Ｃ₄アルコキシ、Ｃ₁〜Ｃ₄ハロアルコキシ、Ｃ₁〜Ｃ₄アルキルチオ、Ｃ₁〜Ｃ₄アルキルスルフィニル、Ｃ₁〜Ｃ₄アルキルスルホニル、Ｃ₁〜Ｃ₄アルキルアミノ、Ｃ₂〜Ｃ₈ジアルキルアミノ、Ｃ₃〜Ｃ₆シクロアルキルアミノ、（Ｃ₁〜Ｃ₄アルキル）（Ｃ₃〜Ｃ₆シクロアルキル）アミノ、Ｃ₂〜Ｃ₄アルキルカルボニル、Ｃ₂〜Ｃ₆アルコキシカルボニル、Ｃ₂〜Ｃ₆アルキルアミノカルボニル、Ｃ₃〜Ｃ₈ジアルキルアミノカルボニルまたはＣ₃〜Ｃ₆トリアルキルシリルであり、
Ｒ⁴はＨまたは場合により置換されていてもよい炭素部分であり、
ＺはＮまたはＣＲ⁵であり、
Ｒ⁵はＨまたはＲ³であり、そして
ｎは０〜３の整数である］
である上記１に記載の方法。
７． Ｒ⁴がＣ₁〜Ｃ₄アルキルである上記６に記載の方法。
８． ＺがＮであり、ｎが１であり、そしてＲ³がＣｌまたはＢｒでありかつ３位に存在する上記７に記載の方法。
９． Ｘ¹がＢｒであり、Ｘ²がＣｌまたはＯＳ（Ｏ）_mＲ¹であり、ｍが２であり、そしてＲ¹がフェニルまたは４−メチルフェニルである上記７に記載の方法。
１０． 式ＩＩＩ

［式中、
Ｘ¹はハロゲンであり、
各Ｒ³は独立してＣ₁〜Ｃ₄アルキル、Ｃ₂〜Ｃ₄アルケニル、Ｃ₂〜Ｃ₄アルキニル、Ｃ₃〜Ｃ₆シクロアルキル、Ｃ₁〜Ｃ₄ハロアルキル、Ｃ₂〜Ｃ₄ハロアルケニル、Ｃ₂〜Ｃ₄ハロアルキニル、Ｃ₃〜Ｃ₆ハロシクロアルキル、ハロゲン、ＣＮ、ＮＯ₂、Ｃ₁〜Ｃ₄アルコキシ、Ｃ₁〜Ｃ₄ハロアルコキシ、Ｃ₁〜Ｃ₄アルキルチオ、Ｃ₁〜Ｃ₄アルキルスルフィニル、Ｃ₁〜Ｃ₄アルキルスルホニル、Ｃ₁〜Ｃ₄アルキルアミノ、Ｃ₂〜Ｃ₈ジアルキルアミノ、Ｃ₃〜Ｃ₆シクロアルキルアミノ、（Ｃ₁〜Ｃ₄アルキル）（Ｃ₃〜Ｃ₆シクロアルキル）アミノ、Ｃ₂〜Ｃ₄アルキルカルボニル、Ｃ₂〜Ｃ₆アルコキシカルボニル、Ｃ₂〜Ｃ₆アルキルアミノカルボニル、Ｃ₃〜Ｃ₈ジアルキルアミノカルボニルまたはＣ₃〜Ｃ₆トリアルキルシリルであり、
ＺはＮまたはＣＲ⁵であり、
Ｒ⁵はＨまたはＲ³であり、
Ｒ⁶はＣＨ₃、Ｆ、ＣｌまたはＢｒであり、
Ｒ⁷はＦ、Ｃｌ、Ｂｒ、ＩまたはＣＦ₃であり、
Ｒ^8aはＣ₁〜Ｃ₄アルキルであり、
Ｒ^8bはＨまたはＣＨ₃であり、そして
ｎは０〜３の整数である］
の化合物を、式Ｉａ

［式中、Ｒ⁴はＨまたは場合により置換されていてもよい炭素部分である］
の化合物を使用して製造する方法であって、
上記６に記載の方法によって式Ｉａの化合物を製造することを特徴とする方法。
１１． Ｒ⁴がＣ₁〜Ｃ₄アルキルである上記１０に記載の方法。
１２． ＺがＮであり、ｎが１であり、そしてＲ³がＣｌまたはＢｒでありかつ３位に存在する上記１１に記載の方法。
１３． Ｘ¹がＢｒであり、Ｘ²がＣｌまたはＯＳ（Ｏ）_mＲ¹であり、ｍが２であり、そしてＲ¹がフェニルまたは４−メチルフェニルである上記１１に記載の方法。 The reaction can be carried out as such or in various suitable solvents including acetonitrile, tetrahydrofuran, diethyl ether, dichloromethane or chloroform at an optimum temperature ranging from room temperature to the reflux temperature of the solvent. The general reaction of benzoxazinones with amines to form anthranilamides is well documented in the chemical literature. For a review on the chemistry of benzoxazinone, see Jakobsen et al., Bioorganic and Medicinal Chemistry 2000, 8, 2095-2103, and references cited therein. See also Coppola, J. Heterocyclic Chemistry 1999, 36, 563-588.

The main aspects and features of the present invention are summarized as follows.
1. Formula I

[Wherein L is an optionally substituted carbon moiety,
Each R is independently selected from optionally substituted carbon moieties;
k is an integer of 0 to 4,
And X ¹ is a halogen]
A 3-halo-4,5-dihydro-1H-pyrazole compound of
Formula II

[Wherein X ² is a halogen other than OS (O) _m R ¹ , OP (O) _p (OR ² ) ₂ or X ¹ ;
m is 1 or 2,
p is 0 or 1,
R ¹ is selected from alkyl and haloalkyl; and phenyl optionally substituted by 1 to 3 substituents optionally selected from alkyl and halogen, and each R ² is independently alkyl and haloalkyl; and Selected from phenyl optionally substituted by 1 to 3 substituents selected from alkyl and halogen]
Or a 4,5-dihydro-1H-pyrazole compound of the formula HX ^{1 in} the presence of a suitable solvent.
2. The method of claim 1, wherein m is 2 and p is 1.
3. The method according to 2 above, wherein X ² is halogen or OS (O) _m R ¹ .
4). The process of claim 3 wherein X ² is Cl or OS (O) _m R ¹ and R ¹ is C ₁ -C ₂ alkyl, phenyl or 4-methylphenyl.
5. The method according to 1 above, wherein X ¹ is Cl or Br.
6). The compound of formula I is of formula Ia

And the compound of formula II is of formula IIa

[Where:
Each R ³ is independently C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ haloalkyl, C ₂ -C ₄ haloalkenyl. C ₂ -C ₄ haloalkynyl, C ₃ -C ₆ halocycloalkyl, halogen, CN, NO ₂ , C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy, C ₁ -C ₄ alkylthio, C _1- C ₄ alkylsulfinyl, C ₁ -C ₄ alkylsulfonyl, C ₁ -C ₄ alkylamino, C ₂ -C ₈ dialkylamino, C ₃ -C ₆ cycloalkylamino, (C ₁ ~C ₄ alkyl) (C ₃ ~ C ₆ cycloalkyl) amino, C ₂ -C ₄ alkylcarbonyl, C ₂ -C ₆ alkoxycarbonyl, C ₂ -C ₆ alkylaminocarbonyl, C ₃ -C ₈ dialkylaminocarbonyl or C ₃ -C ₆ trialkylsilyl Yes,
R ⁴ is H or an optionally substituted carbon moiety,
Z is N or CR ⁵
R ⁵ is H or R ³ and n is an integer from 0 to 3]
The method according to 1 above, wherein
7). The method of claim 6, wherein R ⁴ is C ₁ -C ₄ alkyl.
8). The method of claim 7, wherein Z is N, n is 1, and R ³ is Cl or Br and is in the 3 position.
9. The method of claim 7 wherein X ¹ is Br, X ² is Cl or OS (O) _m R ¹ , m is 2 and R ¹ is phenyl or 4-methylphenyl.
10. Formula III

[Where:
X ¹ is halogen,
Each R ³ is independently C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ haloalkyl, C ₂ -C ₄ haloalkenyl. C ₂ -C ₄ haloalkynyl, C ₃ -C ₆ halocycloalkyl, halogen, CN, NO ₂ , C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy, C ₁ -C ₄ alkylthio, C _1- C ₄ alkylsulfinyl, C ₁ -C ₄ alkylsulfonyl, C ₁ -C ₄ alkylamino, C ₂ -C ₈ dialkylamino, C ₃ -C ₆ cycloalkylamino, (C ₁ ~C ₄ alkyl) (C ₃ ~ C ₆ cycloalkyl) amino, C ₂ -C ₄ alkylcarbonyl, C ₂ -C ₆ alkoxycarbonyl, C ₂ -C ₆ alkylaminocarbonyl, C ₃ -C ₈ dialkylaminocarbonyl or C ₃ -C ₆ trialkylsilyl Yes,
Z is N or CR ⁵
R ⁵ is H or R ³ ,
R ⁶ is CH ₃ , F, Cl or Br;
R ⁷ is F, Cl, Br, I or CF ₃ ;
R ^8a is C ₁ -C ₄ alkyl;
R ^8b is H or CH ₃ and n is an integer from 0 to 3]
The compound of formula Ia

[Wherein R ⁴ is H or an optionally substituted carbon moiety]
A method of producing using a compound of
A process comprising preparing a compound of formula Ia by the process according to claim 6 above.
11. 11. The method according to 10 above, wherein R ⁴ is C ₁ -C ₄ alkyl.
12 12. The method of claim 11, wherein Z is N, n is 1, and R ³ is Cl or Br and is in the 3 position.
13. The method of claim 11, wherein X ¹ is Br, X ² is Cl or OS (O) _m R ¹ , m is 2, and R ¹ is phenyl or 4-methylphenyl.

Claims (3)

Formula I a

[Where:
X ¹ is halogen,
Each R ³ is independently C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ haloalkyl, C ₂ -C ₄ haloalkenyl. C ₂ -C ₄ haloalkynyl, C ₃ -C ₆ halocycloalkyl, halogen, CN, NO ₂ , C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy, C ₁ -C ₄ alkylthio, C _1- C ₄ alkylsulfinyl, C ₁ -C ₄ alkylsulfonyl, C ₁ -C ₄ alkylamino, C ₂ -C ₈ dialkylamino, C ₃ -C ₆ cycloalkylamino, (C ₁ ~C ₄ alkyl) (C ₃ ~ C ₆ cycloalkyl) amino, C ₂ -C ₄ alkylcarbonyl, C ₂ -C ₆ alkoxycarbonyl, C ₂ -C ₆ alkylaminocarbonyl, C ₃ -C ₈ dialkylaminocarbonyl or C ₃ -C ₆ trialkylsilyl Yes,
R ⁴ is H or C ₁ -C ₄ alkyl ;
Z is N or CH and n is an integer from 0 to 3]
A 3-halo-4,5-dihydro-1H-pyrazole compound of
Formula II a

[Where:
X ² is a halogen other than OS (O) _m R ¹ , OP (O) _p (OR ² ) ₂ or X ¹ ;
m is 1 or 2,
p is 0 or 1,
R ¹ is selected from alkyl and haloalkyl; and phenyl optionally substituted by 1 to 3 substituents optionally selected from alkyl and halogen, and each R ² is independently alkyl and haloalkyl; and Selected from phenyl optionally substituted by 1 to 3 substituents selected from alkyl and halogen]
Or a 4,5-dihydro-1H-pyrazole compound of the formula HX ^{1 in} the presence of a suitable solvent. Z is N, n is 1 and a method according to claim 1 wherein R ³ is present and and 3-position is Cl or Br. X ¹ is Br, X ² is Cl or ^{_{OS (O) m R 1,}} m is 2 and A method according to claim 1 R ¹ is phenyl or 4-methylphenyl.